Before human embryonic stem (hES) cell-based therapies (e.g., for such conditions as neuronal disease, cardiovascular disease, diabetes, Parkinson's, among others) can be translated into the clinic, we must develop new strategies that can overcome the immunological barrier. To address this critical bottleneck, we have assembled an interdisciplinary team of investigators who are focused on developing novel and effective strategies to induce immunological tolerance for hES cell therapy. Our ability to overcome the immunological response will be a major scientific advance in stem cell biology. PUBLIC HEALTH RELEVANCE: The goal of our T-R01 proposal is to "re-educate" the immune system toward achieving tolerance of hES cell-based therapies by combining hematopoietic chimerism and thymic regeneration. We have assembled an interdisciplinary team of established investigators with complementary experiences. Here we seek to characterize the immunological profiles of hES cells in an allogeneic "humanized" mouse model;to demonstrate the effectiveness of co-stimulatory blockade strategies for induction of peripheral tolerance to hES cells;and to develop an innovative approach for central tolerance with hemaopoietic chimerism and thymic regeneration. If successful, this achievement will represent a major scientific advancement in hES cell immunology and a significant step toward their eventual clinical translation.